The present invention relates generally to methods and apparatus for treating or controlling medical, psychiatric or neurological disorders by application of modulating electrical signals to a selected nerve or nerve bundle of the patient, and more particularly to techniques for treating patients with migraine by application of such signals to a cranial nerve, using an implantable neurostimulating device. Specifically, the invention is directed toward treating migraine by selective modulation of vagus nerve electrical activity.
Migraine is defined as a recurring vascular headache usually characterized by unilateral onset and severe pain, photophobia, and autonomic disturbances during the acute phase, which may last for hours or days. Classical migraines are associated with a prodromal aura; common migraines do not have a prodrome. The exact mechanism responsible for the disorder is not known, but the head pain is related to dilatation of extracranial blood vessels, which may be the result of chemical changes that cause spasms of intracranial vessels. The prodromes are thought to be related to constriction of the arterioles.
A relationship between migraine and epilepsy is indicated in the literature. See, for example, Basser, Brain (1969) 92:285-300; Hockaday et al., Brain (1969) 92:769-788. Although the two conditions are distinct, they have some areas of commonality. For one thing, patients with migraine are more likely to have epilepsy than those without migraine. For another, many patients with migraine have a strong family history of epilepsy. Other areas of commonality are that both migraine and epilepsy are paroxysmal and involve the brain in either a focal or spreading fashion, and both disorders may be associated with loss of consciousness as well as ictal or interictal EEG abnormalities. A neural disturbance, rather than vascular pathophysiology as the basis for migraine has been proposed by Gordon in Dev. Med. Child. Neurol. 31:682-689. Other reviews and references to specific studies and case reports are cited below.
In Med. Clin. North Am. (1978) 62:571-584, Masland reported finding that many patients with classic and common migraines demonstrate EEG paroxysms, which are seldom seen with cluster and tension headaches. Narbone et al., in Headache (1988) 28:209-211, describe one patient and refer to literature on others who have classical migraine, with seizures intercalated between the prodrome and cephalgia phase of the headache. Twomey et al. reported in Acta Neurol. Scand. (1988) 77:335-338 two cases in which status epilepticus may have immediately followed migraine, with one resulting in death.
The most important similarity between epilepsy and migraine may be and probably is paroxysmal EEG activity. It is unlikely that the cortical electrical activity is merely the result of altered blood flow associated with migraine, since this would probably result in slowing.
Ethical drugs, such as ergotamine and propranolol, have been the treatment of choice for migraine. However, we submit that migraine may share an underlying pathophysiology with epilepsy, and postulate that vagal stimulation can be effective for treating migraine.
In addressing a therapy involving nerve stimulation to treat migraine, observation should be made of existing knowledge that most nerves in the human body are composed of thousands of fibers, having different sizes designated by groups A, B and C, carrying signals to and from the brain and other parts of the body. The vagus nerve, for example, may have approximately 100,000 fibers (axons) of the three different types, each of which carries such signals. Each axon of that nerve only conducts in one direction, in normal circumstances. The A and B fibers are myelinated, that is, they have a myelin sheath in the form of a substance largely composed of fat. On the other hand, the C fibers are unmyelinated.
Myelinated fibers are typically larger, have faster electrical conduction and much lower electrical stimulation thresholds than the unmyelinated fibers. Along with the relatively small amounts of electrical energy needed to stimulate the myelinated fibers, it is noteworthy that such fibers exhibit a particular strength-duration curve in response to a specific width and amplitude of stimulation pulse.
The A and B fibers are stimulated with relatively narrow pulse widths, from 50 to 200 microseconds (.mu.s), for example. A fibers exhibit slightly faster electrical conductivities than the B fibers, and slightly lower electrical stimulation thresholds. The C fibers are relatively much smaller, conduct electrical signals very slowly, and have high stimulation thresholds typically requiring wider pulse widths (e.g., 300-1000 .mu.s) and higher amplitudes for activation. Although the A and B fibers may be selectively stimulated without also stimulating the C fibers, the magnitude and width of the pulse required for stimulating the C fibers would also activate A and B fibers.
Although electrical stimulation of the nerve fiber typically activates neural signals in both directions (bidirectionally), selective unidirectional stimulation is achievable through the use of special nerve electrodes and stimulating waveforms. As noted above, each axon of the vagus nerve normally conducts in only one direction.
In a paper on the effects of vagal stimulation on experimentally induced seizures in rats (Epilepsia (1990) 31 (Supp 2): S7-S19), Woodbury has noted that the vagus nerve is composed of somatic and visceral afferents (i.e., inward conducting nerve fibers which convey impulses toward a nerve center such as the brain or spinal cord) and efferents (i.e., outward conducting nerve fibers which convey impulses to an effector to stimulate it and produce activity). The vast majority of vagal nerve fibers are C fibers, and a majority are visceral afferents having cell bodies lying in masses or ganglia in the neck. The central projections terminate, by and large, in the nucleus of the solitary tract which sends fibers to various regions of the brain (e.g, the hypothalamus, thalamus, and amygdala); others continue to the medial reticular formation of the medulla, the cerebellum, the nucleus cuneatus and other regions.
Woodbury further notes that stimulation of vagal nerve afferent fibers in animals evokes detectable changes of the EEG in all of these regions, and that the nature and extent of these EEG changes depends on the stimulation parameters. Chase, in Exp Neurol (1966) 16:36-49, had also observed that vagal activation can affect the EEG activity of certain parts of the brain. The applicants herein postulate that synchronization of the EEG may be produced when high frequency (&gt;70 Hz) weak stimuli activate only the myelinated (A and B) nerve fibers, and that desynchronization of the EEG occurs when intensity of the stimulus is increased to a level that activates the unmyelinated (C) nerve fibers. Woodbury also observes that vagal stimulation can produce widespread inhibitory effects on seizures and certain involuntary movements.
Extra-physiologic electrical stimulation of the vagus nerve has previously been proposed for treatment of epilepsy and various forms of involuntary movement disorders. Specifically, in U.S. Pat. No. 4,702,254 issued Oct. 27, 1987 to J. Zabara (referred to herein as "the '254 patent"), a method and implantable device are disclosed for alleviating or preventing epileptic seizures, characterized by abnormal neural discharge patterns of the brain. The '254 patent describes an implantable neurocybernetic prosthesis (NCP) which utilizes neurocybernetic spectral discrimination by tuning the external current of the NCP generator to the electrochemical properties of a specific group of inhibitory nerves that affect the reticular system of the brain. These nerves are embedded within a bundle of other nerves, and are selectively activated directly or indirectly by the tuning of the NCP to augment states of brain neural discharge to control convulsions or seizures. According to the patent, the spectral discrimination analysis dictates that certain electrical parameters of the NCP pulse generator be selected based on the electrochemical properties of the nerves desired to be activated. The patent further indicates that the optimum sites for application of the NCP generator output to produce the desired effects are the cranial nerves in general, and the vagus nerve in particular.
The NCP disclosed in the '254 patent may be activated either manually or automatically, to provide treatment for the duration of the seizure Manual activation is performed when the patient experiences the aura at onset of the seizure. Alternatively, automatic activation may be triggered upon detection of instantaneous changes in certain state parameters immediately preceding or at onset of a seizure. Additionally, a prophylactic or preventive mode may be employed in which the NCP is activated periodically to reduce the occurrence and/or the intensity of the seizures. The NCP stimulator of the '254 patent is implanted in the patient's chest and is connected to electrodes installed at the selected point of signal application at the nerve site with the more negative electrode situated closer to the brain and the positive electrode further from the brain, along the vagus nerve.
It is a principal object of the present invention to apply the techniques of selective modulation of vagus nerve electrical activity, using a neurostimulator device which may be implantable, or used external to the body with only a small portion of the circuitry implanted or with only the nerve electrode(s) and associated lead(s) implanted percutaneously in the body, to the treatment of migraine.